Renal disease in the young - genetics, treatment, survival

to adulthood

Prof. Dr. med. Franz Schaefer Nephrologist – Kinderklinik Heidelberg

Heidelberg, Germany

Renal Disease in the Young: Genetics, Treatment, Survival into Adulthood

F.Schaefer Pediatric Nephrology Division Center for Pediatrics and Adolescent Medicine Heidelberg University Hospital

Primary Renal Diagnoses in Children with CKD

4C Study 2011

Kongenitale Anomalien der

Nieren und Harnwege

63%

Glomerulo-pathien

8%

Polyzystische Nieren-

erkrankung 6%

Metabolisch 5%

Nephro-nophtise

4%

HUS 3%

Interstitielle Nephropathie

2%

Nieren-versagen post-ischämisch

1% Vaskulitis

Unbekannt 6%

Andere 2%

Rare Causes of Renal Replacement Therapy

Hypo/dysplasia +/-

refluxive/obstructive uropathy

Cystic dysplasia

Other hereditary NP

HUS

MPGN II

Goodpasture-GN

Alport

FSGS since childhood

Henoch Schonlein NP

Sclerodermia

Tuberculosis

Nephrocalcinosis

Oxalosis Uric acid NP

Chemotherapy

Cryoglobulin NP

Hepatorenal syndrome

Cystinosis

M.Fabry

Balkan NP EDTA Registry (300,000 pts; diagnosis freq < 0.5%)

Rare Nephropathies: “Children’s Diseases”?

0 20 40 60 80 100

Cystinose Oxalose

FSGS seit Kindesalter CAKUT

Andere hereditäre … HUS

Zystische Dysplasie Alport

Schönlein-Henoch MPGN II

Goodpasture Nephrokalzinose

Fabry Leberzirrhose

Kryoglobulin-GN Chemoth.-GN Sklerodermie

Tuberkulose Gicht-NP

Balkan-NP

% Kinder

% Erwachsene

CAKUT

Congenital Anomalies of the Kidney and the Urinary Tract

CAKUT Diagnosis Codes

CAKUT Category Primary Renal Disease Code

Neurogenic PN Pyelonephritis associated with neurogenic bladder 21

Obstructive PN Pyelonephritis due to congenital obstructive uropathy w/o VUR 22

Refluxive PN Pyelonephritis due to VUR without obstruction 24

Hypoplasia Renal hypoplasia (congenital) – unspecified Oligomeganephronic hypoplasia

60 61

Dysplasia Congenital renal dysplasia w/o urinary tract malformation Syndrome of agenesis of abdominal muscles (prune belly)

63 66

Characteristics of RRT Patients in the ERA-EDTA Registry

ALL CAKUT

Renal diagnoses (%)

Hypertensive or diabetic NP 46.9

Unknown / unspecified 19.4

Glomerulonephritis 14.4

Cystic kidney disease 7.1

Vasculitis 2.0

Other 8.0

CAKUT Total 2.2 100

Neurogenic PN 5.6

Obstructive PN 22.9

Refluxive PN 41.9

Hypoplasia 17.3

Dysplasia 12.3

Age

0-4 5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

54-59

60-64

64-69

70-74

Pe

rce

nt

Pa

tien

ts

0

2

4

6

8

10

12

14

16

CAKUT

Other diagnoses

Wühl et al. submitted

Age distribution at start of RRT Percent of patients starting RRT at given age groups

Age

0-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

54-5

9

60-6

4

64-6

9

70-7

4

75-7

9

80-8

485

+

Incid

ence r

ate

of

RR

T (

pm

arp

)

0

1

2

3

4

5neurogenic pyelonephritis

obstructive pyelonephritis

refluxive pyelonephritis

hypoplasia

dysplasia

all CAKUT

Incidence Rate of RRT in CAKUT Patients per million age-related population

Wühl et al. submitted

Cumulative Incidence of RRT in CAKUT Patients

Graft survival Patient survival

Patient and Transplant Outcome after NTx Competing risk analysis for graft and patient survival

P = 0.02 P = 0.007

Time [Years]

0 1 2 3 4 5 6 7 8 9 10

Surv

ival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

neurogenic pyelonephritis

obstructive pyelonephritis

refluxive pyelonephritis

hypoplasia

dysplasia

all CAKUT

Patient Survival on RRT by CAKUT Category

Mortality on RRT

HR (95%CI) p

CAKUT category Dysplasia 1.00

Neurogenic PN 1.66 (1.24-2.21) 0.006

Obstructive PN 0.74 (0.56-0.99) 0.04

Refluxive PN 0.75 (0.57-0.98) 0.04

Hypoplasia 0.73 (0.54-1.00) 0.05

RRT modality at start Pre-emptive Tx 1.00

HD 1.56 (1.04-2.33) 0.03

PD 1.29 (0.85-1.96) 0.23

Age 1.06 (1.06-1.06) <.0001

Female gender 1.09 (0.95-1.25) 0.24

Period after 2000 0.98 (0.86-1.13) 0.81

Patient Mortality in CAKUT

Mortality Rate by Cause of Death

CVD Cancer Infection Other Unknown

Non-CAKUT 1.10 0.26 0.56 0.67 0.69

CAKUT 0.85 0.26 0.57 0.66 0.69

Neurogenic PN 1.79 0.33 1.43 1.89 1.59

Obstructive PN 0.79 0.27 0.52 0.47 0.57

Reflux PN 0.76 0.23 0.51 0.64 0.66

Hypoplasia 1.02 0.23 0.39 0.59 0.73

Dysplasia 0.47 0.25 0.43 0.40 0.36

Steroid Resistant Nephrotic Syndrome

Steroid-sensitive NS

T-cell disorder Circulating

‘permeability’ factor

Steroid-resistant NS

CNI sensitivity Post-tx recurrence

Structural anomalies of glomerular

filtration barrier

Focal Seg Glomerulosclerosis

Diffuse mesangial sclerosis

Minimal Change GN

Early-onset Nephrotic Syndrome:

Nephrin, Podocin, PLCE1,

WT1, LAMB2

Late-onset FSGS:

Actinin 4, TRPC6, INF-2

Structural defects

of slit diaphragm

Loss of cytoskeleton

functions

www.podonet.org

1474 patients registered in 64 centers in 24 countries by July 1, 2012

PodoNet Registry Sites

Turkey33%

Italy20%

Chile4%

Iran3%

Colombia3%

Syria5%

Serbia4%

F,GR,S3%

LT, GE2%

CZ, P, SW1%

Poland 9%

Germany 13%

Age Distribution by Cause

0

50

100

150

200

250

300

genetic

idiopathic

Age (years)

Age Distribution by Cause

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

genetic

idiopathic

Age (years)

Genetic Screening Results

Pts

tested

Pts with

causative mutations

%

positive

NPHS2 920 122 13

WT1 735 38 5

NPHS1 119 25 16

PTPRO 12 5

SMARCAL1 10 4

LAMB2 27 3 15

MYOE1 14 2

NPHS3 52 1 2

INF2 10 2

ACTN4 14 1

TRPC6 14 0

Total 1071 201 18.8

Genetic Screening in 2nd Decade of Life

295 adolescents

with SRNS

72 no DNA available

64 sporadic, 86 AR, 2

AD

10 AD 38 AR 173 sporadic

5/38 (13%)

NPHS2 10/173 (7%)

NPHS2

5/156 (3%)

WT1

3 (1%) syndromic:

1 SMARCAL1, 1

LAMB2,

1 mitoch. tRNA

0/40

INF2

2/10 INF2

1/10 WT1

0/10 TRPC6

0/10 ACTN4

AD: 30%

detection rate

AR: 13%

detection rate

Sporadic: 9%

detection rate

Renal Prognosis by Genetic Disorder

NPHS1

WT1

NPHS2

% p

atie

nts

without

ES

RD

Time from diagnosis (years) Update 7/12

• Myo1E: Podocyte-specific cytoskeleton component localized close to plasma membrane

• 2 out of 29 SRNS families: mutations leading to truncated/mislocated protein

• Age at onset: 1-9 years

• Transient partial response to CsA ?

• PTPRO (=NPHS6): Podocyte specific transmembrane tyrosine phosphatase targeting tight junction proteins nephrin, ZO-1, podocin

• Downregulated in proteinuric nephropathies

• 2 families with splice site mutations: a) skipping of exon 16 b) truncation at exon 19 -> loss of phosphatase activity

• Age at onset: 5-14 years

• 4 of 5 subjects partially responsive to intensified immunosuppression (?)

Am J Hum Genet 2011

Myosin-1E

PTPRO

Efficacy of Treatment Protocols

0% 20% 40% 60% 80% 100%

MPR Pulse

CPH Pulse

CNI

CNI+Pred

CNI+Pred+RAS

CNI+MMF

MMF

Rituximab

RAS

Full remission

Partial remission

No remission

1428 treatment periods in 596 patients

Response to Intensified Immunosuppression Predicts Renal Prognosis

No Remission

Full Remission

Partial Remission

% p

ati

en

ts w

ith

ou

t E

SR

D

Time from diagnosis (years) Update 7/12

Response to Immunosuppressive Therapy by Country

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Complete remission

Partial remission

No response

Response to Calcineurin and RAS Inhibitors by Country

0

10

20

30

40

50

60

70

80

90

% o

f p

ati

en

ts t

reate

d ACE/ARB responsive

CNI responsive

Response to Intensified Immunosuppression

622 patients with medication and proteinuria history

Total n

No remission

Partial remission

Full remission

Genetic 94 88 (95%) 3 (3%) 2 (2%)

Familial 54 33 (61%) 11 (20%) 10 (18%)

Sporadic 474 247 (52%) 64 (14%) 163 (34%)

Total 622 365 (59%) 78 (13%) 172 (28%)

Updated 1/7/2012

Impact of Genetics and Immunology

% p

atie

nts

without

ES

RD

Time from diagnosis (years)

Familial / genetic

Sporadic, multidrug resistant

IS responsive

Update 7/12

Factors Associated with Renal Survival

Hazard Ratio p

Age at start of disease 1.01 0.36

Familial disease 0.89 0.46

Causative NPHS1 mutation 4.06 <0.0001

Causative NPHS2 mutation 1.46 0.04

Causative WT1 mutation 1.03 0.91

Histology (reference: MCN)

DMS 6.95 <0.0001

FSGS 2.00 0.0009

GGS 3.62 0.0002

MPGN 1.22 0.004

Cox Proportional Hazard Analysis

Factors Associated with Renal Survival

Hazard Ratio p

Age at start of disease 1.00 0.97

Familial disease 0.87 0.37

Intensified IS responsive 11.2 <0.0001

Causative NPHS1 mutation 1.56 0.05

Causative NPHS2 mutation 1.08 0.67

Causative WT1 mutation 0.83 0.94

Histology (reference: MCN)

DMS 5.58 <0.0001

FSGS 1.85 0.003

GGS 3.06 0.001

MPGN 1.11 0.71

Cox Proportional Hazard Analysis

Ceylin

Proteinuria, edema since 4th wk of life

Steroid resistant NS

Genetic diagnostics (within 5 days):

Homozygous mutation in NPHS2: P157L

Kidney biopsy cancelled

Immunsuppressants discontinued

Antiproteinuric therapy:

Ramipril+Candesartan

Prognosis:

Progressive CKD

„cure“ by transplantation,

no risk of relapse

Atypical hemolytic uremic syndrome

Endothelium

Activation

Endothelial

Swelling and

Disruption

Platelet

Aggregation

Platelet

Platelet

Activation

Chronic

Uncontrolled

Complement

Activation

Leukocyte

Activation

Platelet Consumption

Mechanical Hemolysis

(Schistocytes)

Blood Clots

Inflammation

Occlusion

Ischemia

Hypoxia

Cell Destruction

Inflammation

Thrombosis

Consequences Consequences

Complement System: Spontaneous Activation and Regulation P

roxim

al

Term

inal

C3

C5

C5a

Potent Anaphylatoxin

Chemotaxis

Proinflammatory

Leukocyte Activation

Endothelial Activation

Prothrombotic

C5b-9 Membrane Attack Complex

Cell Lysis

Proinflammatory

Platelet Activation

Leukocyte Activation

Endothelial Activation

Prothrombotic

Amplification

Natural

Inhibitors –

Immune Complex Clearance

Microbial Opsonization

Anaphylaxis

Inflammation

Thrombosis

C3 + H2O - ALWAYS ACTIVE

(Chronic)

Lectin Pathway Alternative Pathway Classical Pathway

Genetic Complement Disorders in aHUS

-> Autosomal dominant mit inkompletter Penetranz (50%)

-> Oft kombinierte Mutationen verschiedener Kompl.-regulierender Gene

-> Mutationen erklären 50-70% der Fälle

aHUS: Disease Progression Despite PE 3-year-old boy with activating C3 mutation

C5

Pro

xim

al

Te

rmin

al C5a

Eculizumab

Proximal functions of

complement remain intact

– Weak anaphylatoxin

– Immune complex clearance

– Microbial opsonization

Terminal complement - C5a

and C5b-9 activity blocked

Eculizumab binds with high

affinity to C5

Complement Cascade

C5b-9 C5b

C3 C3a

C3b

Eculizumab Blocks Terminal Complement

Nürnberger et al., NEJM 360(5): 542-544. 2009

Eculizumab in Plasma Resistant aHUS 37 yrs female, CFH mutation/deficiency, ESRD, 1st graft lost due to plasma resistant recurrence. 6 wks post 2nd Tx: HUS recurrence

Eculizumab abolished TMA events in >80% of patients

Benefit sustained for >12 months during continued treatment

No new dialysis required

88%

(15/17)

73%

(11/15)

Plasma Sensitive Study Plasma Resistant Study Retrospective

Pediatric Study

Marked Renal Function Improvement by Eculizumab in Plasma-Resistant aHUS

Ch

an

ge f

rom

Baselin

e o

f eG

FR

40

30

20

10

0

-42 0 21 42 70 98 126 154 182

Day

95% CI

eGFR (simple means)

eGFR (estimated 3-piece linear trend)

Eculizumab Intensive

PE/PI

224 252 280 309 336 364

EURenOmics

EURenOmics High-Throughput Research in Rare Kidney Diseases

Project duration: 5 years Funding volume: 12 M€ Partners: 25 academic, 8 industry Disease groups: • Steroid resistant nephrotic syndrome • Membranous nephropathy • Complement disorders (HUS, MPGN, C3 nephropathy) • Tubulopathies • CAKUT

EURenOmics

Technologies

‚Functiomics‘: Cell based assays

ipSC Zebrafish Xenopus

KO/KI mice

High-throughput compound screening

WP

2

W

P3

W

P5

W

P6

W

P4

PodoNet

NIH Neptune

RADAR

ESCAPE Network

EUCAKUT Consortium

aHUS/C3G Consortium

EUNEFRON

ERCB Renal cDNA Bank

Membranous NP Consortium

IRDiRC Goals:

Personalized Prediction, Diagnosis and Therapies for Patients with Rare Diseases

Targeted Output Molecular

disease ontologies

Rapid diagnostic

tests

Drug candidate compounds

Novel biomarkers

Models to support trials

Phenotype standardization

Reference -omics profiles

Sustainable resources

Exome sequencing

Transcriptomics: Expression profiling

ChipSeq

Proteomics

miRNAomics

Epitope screening

WP7

Metabolomics

Multilevel integrative

bio-informatics